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Treatment of chronic systolic heart failure secondary to Chagas heart disease in the current era of heart failure therapy
Treatment of chronic systolic heart failure secondary to Chagas heart disease in the current era of heart failure therapy Reinaldo B. Bestetti, MD, PhD, FESC, a Tatiana A.D. Theodoropoulos, MD, PhD, a Augusto Cardinalli-Neto, MD, PhD, a and Patrı´cia M. Cury, MD, PhD b São José do Rio Preto City, Brazil
The treatment of chronic heart failure secondary to Chagas disease has been based on extrapolation of data achieved in the treatment of non–Chagas disease heart failure. Because β-blockers decrease the incidence of sudden cardiac death in non–Chagas disease heart failure and sudden cardiac death occurs preferentially in patients with mild Chagas disease heart failure, β-blockers may be administered first to class I/II patients with Chagas disease heart failure. In advanced Chagas disease heart failure, angiotensin-converting enzyme inhibitor and diuretics may be given at first to compensate for congestive symptoms. After clinical status improvement, β-blockers should be given at targeted doses, if necessary reducing angiotensin-converting enzyme inhibitor doses. Primary and secondary prevention of sudden cardiac death may be accomplished with implantable cardioverter defibrillators because of the high recurrence of life-threatening arrhythmias despite amiodarone administration. In refractory heart failure, heart transplantation is the treatment of choice. (Am Heart J 2008;156:422-30.)
Although a marked decrease in the incidence of Chagas disease has been observed in the past decade in many countries of South America,1 it still is a major health problem and no longer confined to the American continent because of international immigration. In fact, about 100 million people are at risk of acquiring Chagas disease, 18 million are estimated to have the disease, and about 50,000 die of Chagas disease annually in South America.2 Chagas disease is caused by the protozoan Trypanosoma cruzi, which is transmitted to humans through the feces of a reduvidii bug.1 Chagas cardiomyopathy is the most frequent clinical manifestation of Chagas disease, affecting about 30% of infected patients 10 to 20 years after initial infection.3 Chronic heart failure, sudden cardiac death, thromboembolism, arrhythmias and atrioventricular blocks, and chest pain are the protean clinical manifestations of Chagas cardiomyopathy.3-5 Chagas cardiomyopathy is the leading cause of chronic systolic heart failure in areas where the disease
From the aOutpatient Cardiomyopathy Service, Division of Cardiology, and bDepartment of Pathology, Hospital de Base, São José do Rio Preto Medical School, São José do Rio Preto City, Brazil. Submitted November 2, 2007; accepted April 29, 2008. Reprint requests: Reinaldo B. Bestetti, MD, PhD, Hospital de Base, Setor de Eletrocardiografia, Av. Faria Lima, 5544; 15090-000 São José do Rio Preto City, Brazil. E-mail: [email protected] 0002-8703/$ - see front matter © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.04.023
is endemic.6 Chronic heart failure secondary to Chagas cardiomyopathy affects 4% to 8% of outpatients living in areas where the disease is endemic,7,8 10% of patients of a hospital-based sample of a secondary referral center, and up to 76% of patients from a hospitalderived cohort of a tertiary referral center.9,10 The incidence of chronic heart failure in hospital-based cohorts is about 3% annually.11 To date, no randomized, double-blinded, placebocontrolled clinical trial evaluating the impact of a treatment modality on survival has been conducted on patients with Chagas disease heart failure. Thus, no evidence-based guideline to treat Chagas disease heart failure exists. In this overview, we focus on strategies to properly treat patients with Chagas disease heart failure in the contemporary era of heart failure treatment.
Search strategy and selection criteria We did a search in PubMed (www.pubmed.gov) for randomized trials evaluating mortality in patients with chronic heart failure secondary to Chagas cardiomyopathy from 1965 onward. We also did a search looking for articles dealing with treatment of chronic heart failure secondary to Chagas cardiomyopathy. We linked search terms “heart failure” and “treatment” with “Chagas' disease.” We ruled out articles that reported data for Chagas and non–Chagas disease heart failure. We identified 25 articles on Chagas disease heart failure treatment, which formed the basis of this work.
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Figure 1
A, Gross aspect of the heart from a patient with chronic heart failure secondary to Chagas cardiomyopathy showing right and left ventricular dilatation as well as left ventricular apical aneurysm (*). B, Histologic aspect of an explanted heart from a patient with end-stage chronic heart failure secondary to Chagas cardiomyopathy who had been treated with benznidazol. A chronic inflammatory infiltrate composed mainly of lymphocytic cells associated with foci of interstitial fibrosis can be seen (hematoxylin-eosin, original magnification ×100).
Pathophysiology of chronic heart failure secondary to Chagas cardiomyopathy The gross aspect of the heart in Chagas disease heart failure is characterized by chamber dilatation, mural thrombosis, and left ventricular apical aneurysm in the absence of concomitant obstructive coronary artery disease. The presence of the apical aneurysm poses patients with Chagas disease to an additional risk because life-threatening ventricular arrhythmias may arise from this site (Figure 1, A). Histologically, autopsy material12 as well as explanted hearts from patients with Chagas disease heart failure have revealed extensive foci of reparative fibrosis associated with chronic myocardial inflammation intermingled with areas of normal myocardium throughout the heart. Interestingly, T cruzi is seldom seen in the myocardium, as shown in Figure 1, B. As a result of this remodeling process, an irreversible systolic pump failure ensues, thus leading to neurohormonal activation. Increased levels of plasma renin activity and plasma noradrenaline, similar to those found in non–Chagas disease heart failure, have been observed in patients with chronic heart failure due to Chagas disease.13-15 In view of cardiac parasympathetic destruction,12 intracardiac autonomic dysfunction also occurs. In fact, increased release of adrenaline from the coronary sinus has been detected in patients with Chagas disease as compared to patients with non–Chagas disease heart failure.15 This might facilitate noradrenaline myocardial uptake,16 resulting in increased myocardial toxicity and subsequent ventricular remodeling, as observed in a rat model of catecholamine cardiomyopathy.17 Collectively, therefore,
these findings suggest that the neurohormonal profile of Chagas disease heart failure is similar to that seen in non– Chagas disease heart failure.
Clinical course of patients with Chagas disease heart failure Left-sided chronic heart failure is the most frequently found manifestation of Chagas disease heart failure, followed by bi-sided heart failure, sometimes with the predominance of right ventricular signs.3 Echocardiography usually reveals left ventricular dilatation, left ventricular systolic dysfunction, left ventricular apical aneurysm, and mural thrombus.18 A clinical picture consistent with overt isolated diastolic heart failure has not been detected in Chagas disease. Predictors of mortality for the subset of patients with Chagas disease heart failure are scanty. Systolic blood pressure, left ventricular ejection fraction, and maximal oxygen consumption rate have been found to be independent predictors of mortality for patients with Chagas disease with chronic heart failure.10,19,20 In the contemporary era of heart failure treatment, a prospective longitudinal cohort study carried out at our institution showed that lack of β-blocking agent use, left ventricular ejection fraction, New York Heart Association class IV, serum sodium levels, and digoxin use were independent predictors of all-cause mortality for patients with chronic heart failure due to Chagas disease.21 Outcome of patients with chronic heart failure secondary to Chagas cardiomyopathy is relentless and poorer than that observed in those with non–Chagas disease heart failure. An annual mortality rate as high as
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Table I. Major relevant studies evaluating neurohormonal axis, left ventricular function, and hemodynamic parameters carried out on patients with chronic heart failure due to Chagas disease Author No. of patients Year of publication Type of study Treatment intervention Duration of study Outcome
Roberti et al24
Szajnbock et al25
Botoni et al26
Davila et al28
Manço et al33
Khoury et al34
15 1992 RPCT
20 1993 NRCT
9 2002 UCS
10 1974 UCS
13 1996 NRCT
Captopril, 150 mg/d
Ena, 5-10 mg/d
42 2007 Ena: UCS; Car: RPCT Ena: 40 mg/d; Car: 50 mg/d
Metoprolol, 50 mg/d
IV lanatosideo C 0.4-1.2 mg
6 wk Decreased HR, UNE, couplets/ 24 h (P b .05).
8 wk Decreased E/A wave
Metil digoxina: 0.02 mg/kg; 6/6 for 24 h 24 h Decreased PNE (P b .008), PAldo (P b .01)
16 wk 10 wk 1h Increased LVEF Decreased PCWP, Phase 1: Ena (P b .05), decreased increased CO increased LVEF LVSD (P b .04) (P = .02), decreased serum BNP (P = .03),
RPCT, Randomized placebo controlled trial; NRCT, nonrandomized controlled trial; Ena, enalapril; UCS, uncontrolled study; Car, carvedilol; IV, intravascular; HR, heart rate (beat/ min); UNE, urinary norepinephrine (pg/mL); E/A, relation between waves E and A on Doppler echocardiography; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure (mm Hg); LVSD, left ventricular systolic dimension; CO, cardiac output (L/min); PNE, plasma norepinephrine (pg/mL); PAldo, plasma aldosterone (pg/mL).
20% may be observed in patients with this condition20 even in the contemporary era.21
Management of patients with Chagas disease with chronic heart failure
heart failure secondary to Chagas cardiomyopathy who tolerate target doses of angiotensin-converting enzyme inhibitors (ACEIs)6 and perhaps β-blocking agent therapy.23 Therefore, control of dietary sodium ingestion should be made with some caution in patients with Chagas disease heart failure.
Nonpharmacological treatment A major point of attention regarding the dietetic regimen of patients with chronic heart failure secondary to Chagas cardiomyopathy is related to magnesium ingestion. In fact, low serum magnesium levels can be found in about 33% of patients with chronic heart failure secondary to Chagas cardiomyopathy, whereas the percentage of patients with this condition with low muscle magnesium content is still higher (66%). In these patients, low magnesium levels have been associated with either clinical signs of digitalis toxicity or lifethreatening ventricular arrhythmias on the 12-lead electrocardiogram.22 Because patients with Chagas disease are usually from a low socioeconomic class, thus having a high likelihood of poor nutrition, mainly during episodes of overt heart failure, a dietetic regimen rich in magnesium content would be desirable to patients with chronic Chagas disease heart failure. Another aspect that deserves further consideration is salt ingestion restriction. A low-sodium diet has frequently been used in the treatment of Chagas disease heart failure. Nonetheless, low levels of systemic arterial pressure have usually been found in patients with Chagas disease in comparison to patients with non– Chagas disease heart failure.23 Because patients with chronic heart failure usually have increased urinary sodium losses, salt ingestion reduction may further decrease low serum sodium levels, thus predisposing patients with Chagas disease heart failure to systemic arterial hypotension. This fact might account, at least in part, for the low percentage of patients with chronic
Pharmacological treatment Angiotensin-converting enzyme inhibitors have largely been used in the treatment of patients with chronic heart failure secondary to Chagas cardiomyopathy. However, a few studies have evaluated the role of ACEIs in the treatment of patients with Chagas disease with chronic heart failure. A randomized trial conducted on New York Heart Association class IV patients has shown a beneficial effect of captopril on decreasing heart rate, urinary catecholamine levels, plasma renin activity, and ventricular couplets (Table I). A similar beneficial effect of enalapril on left ventricular diastolic function has been reported by Szajnbock et al25 (Table I). Botoni et al26 recently reported that high doses of enalapril increase left ventricular ejection fraction, improve quality of life, and decrease serum brain natriuretic peptide (BNP) and chemokines levels, as shown in Table I. β-Blocking agents are promising in the treatment of Chagas disease heart failure. Experimentally, metoprolol was able to reverse eletrocardiographic changes consistent with T cruzi–induced rat chronic Chagas heart disease.27 Davila et al28 clearly demonstrated that longterm small doses of metoprolol improved clinical status, increased systemic arterial pressure, and increased left ventricular systolic function in the midterm follow-up (Table I). Recently, Botoni et al26 have shown a marginal positive effect of carvedilol on left ventricular ejection fraction after the renin-angiotensin system blocking (Table I). Importantly, neither bradycardia nor systemic arterial hypotension was reported in such studies.26,28
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After having blocked the renin-angiotensin system with captopril in patients with chronic heart failure secondary to Chagas cardiomyopathy, we were able to add β-blockers only to 37% of such patients because of the appearance of symptomatic systemic arterial hypotension.21 Our results are in line with those reported by Braga et al,23 who were able to give β-blocking agents only to 39% of patients with chronic heart failure secondary to Chagas cardiomyopathy. Thus, it is conceivable that a general, unselected population of patients with Chagas disease heart failure, in contrast to patients with non–Chagas disease enrolled in randomized clinical trials, will not be able to tolerate the target doses of β-blockers and ACEIs used in major trials. Based on these facts, and because sudden cardiac death is more frequently observed in patients with Chagas disease with mild chronic heart failure than in those with advanced chronic heart failure,11 ACEIs increase left ventricular ejection fraction mainly in patients with a basal left ventricular ejection fraction b45%,26 β-blockers may decrease sudden cardiac death in non–Chagas disease heart failure,29 and treatment of heart failure can be initiated with either ACEI inhibitors or β-blockers in the setting of non–Chagas disease heart failure.30 It is conceivable that β-blockers might be administered firstly than ACEIs in New York Heart Association Functional class I and II patients with Chagas disease in. Because the neurohormonal activation is similar to that found in non– Chagas disease heart failure, it is reasonable to achieve target doses of β-blockers (50 mg/d to carvedilol, 200 mg/d to metoprolol CR/XL, and 10 mg/d to bisoprolol) in patients with Chagas disease heart failure. In the case patients are not able to tolerate these doses because of side effects (symptomatic systemic arterial hypotension and/or drug-induced asthma and/or renal failure), daily doses of such drugs should be reduced. The β-blocking agent should be withdrawn only if side effects still persist. Nonetheless, we concede that such a proposition needs to be tested in a prospective randomized trial. In patients with advanced chronic heart failure secondary to Chagas cardiomyopathy (New York Heart Association classes III or IV), furosemide is usually necessary to alleviate congestive symptoms. Nonetheless, the potential negative impact of long-term furosemide administration has never been appreciated in these patients. Furthermore, ACEIs might be given first than a βblocking agent not only because of the safety and efficacy of ACEIs in patients with Chagas cardiomyopathy with advanced heart failure but also because of the potential for β-blockers to aggravate congestive symptoms in patients with this condition. As previously discussed, it is conceivable that up to 60% of patients will not be able to tolerate a β-blocker agent after a target dose of ACEI (enalapril = 20 mg/d, captopril = 75 mg/d) is achieved. In this circumstance, it might be necessary to reduce the
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daily dose of ACEI in order that the β-blocker agent could be given. This approach might be supported by studies showing that small doses of ACEI have the same beneficial impact on mortality than target doses used in trials enrolling patients with non–Chagas disease heart failure.31,32 It is noteworthy that a daily dose of carvedilol as low as 6.25 mg may have a protective effect in patients with Chagas cardiomyopathy with chronic heart failure.21 Spironolactone combined with ACEI has recently been demonstrated to have a beneficial effect on the neurohormonal activation in patients with mild heart failure due to Chagas disease.26 It is unclear whether spironolactone would be beneficial to patients with chronic heart failure secondary to Chagas cardiomyopathy not taking ACEIs. In non–Chagas disease heart failure, it is now well established that spironolactone administration improves survival. Although no study evaluating the effects of spironolactone in patients with advanced heart failure due to Chagas disease is available, it would be reasonable to administer it to patients with advanced and milder forms of Chagas disease heart failure, mostly if in combination with ACEIs. Digoxin is another drug that has long been used in the treatment of patients with advanced chronic heart failure secondary to Chagas cardiomyopathy. Acute digitalization produces a salutary effect on the hemodynamic parameters, decreasing right atrium pressure, right ventricular pressure, and pulmonary capillary wedge pressure and increasing systemic arterial pressure and cardiac output.33 Furthermore, acute digoxin administration has been shown to decrease plasma levels of noradrenaline, aldosterone, and renin activity.34 Nonetheless, potential for toxicity is great in patients with chronic heart failure due to Chagas disease in view of the severity of underlying myocardial lesions throughout the myocardium12 as well as the compromise of the cardiac conducting system.3 In clinical practice, however, neither advanced atrioventricular block nor ventricular arrhythmias have been observed in patients with chronic heart failure due to Chagas disease on chronic digital use whenever this drug is given cautiously.35 However, a recent observational study has shown that chronic digoxin use is a predictor of all-cause mortality.21 Thus, measurement of digoxin serum levels would be desirable in patients with Chagas disease heart failure treated with digoxin. Anticoagulation to prevent stroke remains controversial in patients with Chagas disease heart failure. The incidence of cardioembolic stroke is low in a general, unselected hospital-based cohort of patients with chronic Chagas heart disease.36 Carod-Artal et al37 have shown that left ventricular apical aneurysm, heart failure, and arrhythmias are major contributors to independently predict stroke in patients with chronic Chagas disease. Studies performed specifically in patients with chronic heart failure due to Chagas disease are virtually lacking.
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Figure 2
Electrogram from a patient with Chagas disease heart failure treated with ICD. Nonsustained VT was detected on 24-hour Holter monitoring, and an inducible episode of sustained VT was found at electrophysiologic testing. An episode of VF during follow-up, not preceded by sustained VT, can be seen. AF, Atrial fibrillation.
Thus, at the present time, taking into consideration the cost-effectiveness of anticoagulation in patients with low socioeconomic status, it would be prudent to recommend anticoagulation to patients with Chagas disease heart failure with left ventricular apical aneurysm with mural thrombus, atrial fibrillation, or previous stroke. Benznidazol has been claimed to have a beneficial effect on disease progression in patients with Chagas disease.38 However, no study has addressed the role of benznidazol in patients with chronic Chagas disease chronic heart failure.
Surgical treatment Another major point in the treatment of patients with chronic heart failure secondary to Chagas cardiomyopathy is sudden cardiac death prevention. In this regard, electrophysiologic testing is crucial to mortality risk stratification and proper treatment to avert sudden cardiac death. Another potential tool to properly manage sudden cardiac death in patients with Chagas disease heart failure is heart rate variability. Heart rate variability measurements are well-established predictors of total mortality and sudden cardiac death in patients with non– Chagas disease heart failure.39 Nonetheless, the value of heart rate variability to predict cardiac death in patients
with Chagas disease with chronic heart failure has not yet been established. It would be desirable to measure indices of heart rate variability in patients with this condition not only to refine mortality risk stratification but also to guide the impact of therapeutic modalities on autonomic dysfunction. Nonsustained ventricular tachycardia (VT), which has been detected in 89% of patients with Chagas cardiomyopathy with chronic heart failure,40 has been shown to be a predictor of all-cause mortality in patients with mild9 left ventricular dysfunction secondary to Chagas cardiomyopathy. Induction of sustained VT at programed ventricular stimulation in patients with Chagas disease heart failure with nonsustained VT receiving amiodarone or sotalol predicts a dismal prognosis.41 Thus, the efficacy of amiodarone for primary prevention of sudden cardiac death in patients with Chagas disease heart failure is limited. This might be explained by ventricular fibrillation (VF) not preceded by degeneration of sustained VT can be found in up to 37% of patients with chronic Chagas heart disease42 despite amiodarone therapy in contrast to what has been observed in patients with non–Chagas disease. In addition, in non–Chagas disease heart failure, amiodarone has been shown to have no beneficial effect on all-cause mortality.43 Based on these facts, it is
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plausible to recommend implantable cardioverter defibrillator (ICD) therapy for primary prevention of sudden cardiac death in patients with Chagas disease with chronic heart failure and a left ventricular ejection fraction b30% because of the high risk of primary VF, as shown in Figure 2, and in keeping with current guidelines for non–Chagas disease dilated cardiomyopathy. In patients with left ventricular ejection fraction N30% and nonsustained VT at Holter monitoring, however, sudden death risk stratification with electrophysiologic testing is paramount. Those patients with inducible VT might be better treated with ICD. For the remaining patients, amiodarone should be given to those with arrhythmiainduced symptoms. Sustained VT is a frequent complication of chronic Chagas heart disease.44 Almost all patients will experience resurgence of life-threatening ventricular arrhythmias, including VF, within 2 years of the index event despite treatment with amiodarone and/or a β-blocking agent.42 Furthermore, in patients with Chagas disease with life-threatening ventricular arrhythmias, sudden cardiac death may be prevented by ICD therapy.45 Thus, ICD therapy seems to be preferable for secondary prevention of sudden cardiac death for patients with chronic heart failure due to Chagas disease. However, when this device-based therapy is unavailable, an alternative approach is to give amiodarone and βblocking agent, followed by an electrophysiologic testing. Patients with no inducible life-threatening ventricular arhythmias or those with inducible VT well tolerated hemodynamicaly may not receive ICD therapy.46 Data concerning resyncronization therapy in Chagas disease heart failure are lacking. At the present time, it would be reasonable to offer resyncronization therapy for patients with advanced chronic heart failure due to Chagas disease, proper medical therapy (target doses of β-blockers and ACEI), lengthening of the QRS complex N120 milliseconds on 12-lead electrocardiogram, and documenting intraventricular dyssyncrony on Tissue Doppler Imaging, as recommended for patients with non–Chagas disease heart failure. Orthotopic heart transplantation is a feasible treatment for selected patients with refractory heart failure secondary to Chagas cardiomyopathy. One study has shown that the median number of bacterial infection episodes per patient is 0.5 in Chagas heart transplant recipients and 1.0 in non–Chagas heart transplant recipients (P b .05). Therefore, the incidence of infection after heart transplantation is lower in Chagas than in non– Chagas heart transplant recipients.47 Perhaps this fact may account, at least in part, for why outcome after heart transplantation is better in Chagas than in non–Chagas heart transplant recipients.48 Vilas-Boas et al49 implanted bone marrow stem cells in the myocardium of 28 patients with refractory chronic heart failure secondary to Chagas cardiomyopathy. They
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Table II. Potential differences in the treatment of patients with Chagas disease heart failure in comparison to patients with non– Chagas disease heart failure
Diet rich in magnesium content Spironolactone in combination with ACEI to NYHA class I/II patients Low tolerability to ACEI target doses β-Blocker first than ACEI CRT efficacy ICD therapy for patients with LVEF N30%, NYHA class I/II, and inducible VT
Chagas disease
Non–Chagas disease
Necessary Yes
Unknown Unknown
Yes Yes Unknown Yes
No Likely Yes Controversial
NYHA, New York Heart Association; CRT, cardiac resyncronization therapy; LVEF, left ventricular ejection fraction.
have observed a modest increase in left ventricular ejection fraction, improvement in clinical status, improvement in indices of quality of life, and an increase in the distance walked during 6 minutes 2 months after the procedure. Whether stem cell implantation will have a place in the treatment of Chagas disease heart failure remains to be determined. Table II summarizes potential differences in the management of patients with Chagas disease heart failure in comparison to patients with non–Chagas disease heart failure. Figure 3 illustrates our suggestion to treat patients with chronic heart failure due to Chagas disease. Class I patients may be identified with either echocardiography18 or BNP50 measurements in areas where the disease is endemic. However, in distant, rural areas, where the conduct of such tests is not feasible, clinical status and/or male sex may be of value to identify asymptomatic left ventricular dysfunction.51 Such patients may be firstly treated with β-blockers, as recommended for non–Chagas disease asymptomatic left ventricular dysfunction. Class II patients may also be given β-blockers first, not only to block the ventricular remodeling process but also to avert sudden cardiac death. Class III patients should initially be treated with diuretics, ACEIs, and if really necessary, digoxin (with monitoring of digoxin serum levels). After clinical compensation, a β-blocking agent must be added to treatment. Class IV patients must be treated with diuretics, ACEI, and digoxin. In refractory class IV symptoms, intravenous sodium nitroprusside may replace ACEI to further decrease left ventricular enddiastolic pressure and ameliorates congestive symptoms. Primary prophylaxis of sudden cardiac death in patients with a left ventricular ejection fraction b30% may be accomplished with ICD treatment. Patients with a left ventricular ejection fraction N30% and nonsustained VT should undergo electrophysiologic testing. In those patients with inducible life-threatening ventricular arrhythmias, ICD-based therapy may be useful. Anticoagulation is warranted by patients with left ventricular
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Figure 3
Suggestion of a strategy to treat patients with Chagas disease with chronic heart failure. LVEF, Left ventricular ejection fraction; NSVT, nonsustained VT; EPT, electrophysiologic testing; Dys, dyssynchrony; RCT, resynchronization therapy.
apical aneurysm with a mural thrombus, atrial fibrillation, and/or a previous stroke.
Conclusions Treating Chagas disease heart failure is a major challenge for physicians working in areas where the disease is endemic because of lack of evidence-based medicine support to improve survival. Target doses of βblockers and ACEIs achieved in major trials conducted on
patients with non–Chagas disease are the mainstay of pharmacological treatment of patients with chronic heart failure due to Chagas disease . Primary and secondary prevention of sudden cardiac death can be accomplished with ICD therapy. Heart transplantation is the preferable treatment for patients with end-stage heart failure. We are indebted to Adília Maria Pires Sciarra, MSc, for revising the English text.
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References 1. UNICEF-UNDP-World Bank-World Health Organization Special Programme for Research and Training in Tropical Diseases. Available at www.who.int/tdr/diseases/Chagas [Last accessed on September 11, 2007]. 2. Chagas' disease—an epidemic that can no longer be ignored. Lancet 2006;368:619. 3. Laranja FS, Dias E, Nóbrega G, et al. Chagas' disease. A clinical, epidemiologic, and pathologic study. Circulation 1956;14: 1035-60. 4. Oliveira JSM, Araujo RC, Navarro MA, et al. Cardiac thrombosis and thromboembolism in chronic Chagas' heart disease. Am J Cardiol 1983;52:147-51. 5. Bestetti RB, Ariolli MT, Carmo JL, et al. Clinical characteristics of acute myocardial infarction in patients with Chagas' disease. Int J Cardiol 1992;35:371-6. 6. Bestetti RB, Muccillo G. Clinical course of Chagas' heart disease: a comparison with dilated cardiomyopathy. Int J Cardiol 1997;60: 187-93. 7. Coura JR, Pereira JB. A follow up evaluation of Chagas' disease in two endemic areas in Brazil. Mem Inst Oswaldo Cruz 1984;79 (Suppl 1):107-12. 8. Acquatella H, Catalioti F, Mancero JG, et al. Long-term control of Chagas' disease in Venezuela: effects of serologic findings, electrocardiographic abnormalities, and clinical outcome. Circulation 1987;76:556-62. 9. Rassi Jr A, Rassi A, Little WC, et al. Development and validation of a risk score for predicting death in Chagas' heart disease. N Engl J Med 2006;355:799-808. 10. Bestetti RB, Dalbo CMR, Arruda CA, et al. Predictors of sudden cardiac death for patients with Chagas' disease: a hospital-derived cohort study. Cardiology 1996;87:481-7. 11. Espinosa R, Carrasco HA, Belandria F, et al. Life expectancy analysis in patients with Chagas' disease: prognosis after one decade (19731983). Int J Cardiol 1985;8:45-56. 12. Bestetti RB, Rossi MA. A rationale approach for mortality risk stratification in Chagas' heart disease. Int J Cardiol 1997;58: 199-209. 13. Bellabarba G, Davila DH, Torres A, et al. A Serum renin activity in chagasic patients with and without congestive heart failure. Int J Cardiol 1994;47:5-11. 14. Davila DF, Bellabarba G, Hernandez L, et al. Serum norepinephrine, myocardial damage, and left ventricular systolic function in Chagas' heart disease. Int J Cardiol 1995;52:145-51. 15. Bestetti RB, Coutinho-Neto J, Staibano L, et al. Peripheral and coronary sinus catecholamine levels in patients with severe congestive heart failure due to Chagas' disease. Cardiology 1995; 86:202-6. 16. Kaye DM, Lefkovitz J, Cox H, et al. Regional epinephrine kinetics in human heart failure: evidence for extra-adrenal, nonneural release. Am J Physiol 1995;269:H182-8. 17. Bestetti RB, Ramos CP, Figueredo-Silva J, et al. Ability of the electrocardiogram to detect myocardial lesions in isoproterenolinduced rat cardiomyopathy. Cardiovasc Res 1987;21:916-21. 18. Acquatella H. Echocardiography in Chagas' heart disease. Circulation 2007;115:1124-31. 19. Espinosa RA, Pericchi LR, Carrasco HA, et al. Prognostic indicators of chronic chagasic cardiopathy. Int J Cardiol 1991;30:195-202. 20. Mady C, Cardoso RH, Barreto ACP, et al. Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy. Circulation 1994;90:3098-102.
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21. Theodoropoulos TAD, Bestetti RB, Otaviano AP, et al. Predictors of allcause mortality in chronic Chagas' heart disease in the current era of heart failure therapy. Int J Cardiol 2008;128:22-9. 22. Câmara EJN, Cruz TRP, Nassri JM, et al. Muscle magnesium content and cardiac arrhythmias during treatment of congestive heart failure due to chronic chagasic cardiomyopathy. Braz J Med Biol Res 1986; 19:49-58. 23. Braga JCV, Reis F, Aras R, et al. Aspectos clínicos e terapêuticos da Insuficiência Cardíaca por doença de Chagas. Arq Bras Cardiol 2006;86:297-302. 24. Roberti RR, Martinez EE, Andrade JL, et al. Chagas' cardiomyopathy and captopril. Eur Heart J 1992;13:966-70. 25. Szajnbock FEK, Barretto ACP, Mady C, et al. Ação benéfica do enalapril sobre a função diastólica ventricular na Miocardiopatia da doença de Chagas. Arq Bras Cardiol 1993;60:273-8. 26. Botoni FA, Poole-Wilson PA, Ribeiro ALP, et al. A randomized trial of carvedilol after renin-angiotensin system inhibition in chronic Chagas' cardiomyopathy. Am Heart J 2007;153:544-8. 27. Bestetti RB, Sales-Neto VN, Pinto LZ, et al. Effects of long term metoprolol administration on the electrocardiogram of rats infected with T. cruzi. Cardiovasc Res 1990;24:521-5. 28. Davila DF, Angel F, Bellabarba GA, et al. Effects of metoprolol in chagasic patients with severe congestive heart failure. Int J Cardiol 2002;85:255-60. 29. Merit-HF Study group. Effect of metoprolol CR/XL in chronic heart failure. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7. 30. Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril as compared with the opposite sequence. Circulation 2005;112:2426-35. 31. Network investigators. Clinical outcome with enalapril in symptomatic chronic heart failure: a dose comparison study. Eur Heart J 1998;19:481-9. 32. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS study group. Circulation 1999;100: 3212-8. 33. Manço JC, Gallo Jr L, Godoy RA, et al. Efeitos hemodinâmicos do digital na Cardiopatia Chagásica Crônica. Arq Bras Cardiol 1974; 27:25-35. 34. Khoury AM, Davila DF, Bellabarba G, et al. Acute effects of digitalis and enalapril on the neurohormonal profile of chagasic patients with severe congestive heart failure. Int J Cardiol 1996;57: 21-9. 35. Barretto ACP, Pileggi FJC. Digital na cardiopatia chagásica. Arq Bras Cardiol 1982;38:283-9. 36. Bestetti R. Stroke in a hospital-derived cohort of patients with chronic Chagas' heart disease. Acta Cardiol 2000;55:33-8. 37. Carod-Artal FJ, Vargas AP, Horan TA, et al. Chagasic cardiomyopathy is independently associated with ischemic stroke in Chagas' disease. Stroke 2005;36:965-70. 38. Viotti R, Vigliano C, Lococo B, et al. Long-term outcomes of treating chronic Chagas' disease with benznidazole versus no treatment. Arch Int Med 2006;144:724-34. 39. Sandercock GRH, Brodie DA. The role of heart rate variability in prognosis for different modes of death in chronic heart failure. Pac Clin Electrophysiol 2006;29:892-904. 40. Rassi Jr A, Rassi AG, Rassi SG, et al. Arritmias ventriculares na doença de Chagas. Particularidades diagnósticas, prognósticas e terapêuticas. Arq Bras Cardiol 1995;65:377-87.
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41. Silva RMFL, Távora MZP, Gondim FAA, et al. Predictive value of clinical and electrophysiological variables in patients with chronic chagasic cardiomyopathy and non-sustained ventricular tachycardia. Arq Bras Cardiol 2000;75:41-7. 42. Cardinalli-Neto A, Greco OT, Bestetti RB. Automatic implantable cardioverter-defibrillators in Chagas' heart disease patients with malignant ventricular arrhythmias. Pacing Clin Electrophysiol 2006; 29:467-70. 43. Bardy G, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37. 44. Bestetti RB, Santos CRF, Machado Jr OB, et al. Clinical profile of patients with Chagas' disease before and during ventricular tachycardia. Int J Cardiol 1990;29:39-46. 45. Cardinalli-Neto, Bestetti RB, Cordeiro JA, et al. Predictors of all-cause mortality for patients with chronic Chagas' heart disease receiving implantable cardioverter defibrillator therapy. J Cardiovasc Electrophysiol 2007;18:1236-40.
46. Leite LR, Fenelon G, Simões Jr A, et al. Clinical usefulness of electrophysiologic testing in patients with ventricular tachycardia and chronic chagasic cardiomyopathy treated with amiodarone or sotalol. J Cardiovasc Electrophysiol 2003;14:567-73. 47. Bestetti RB, Souza TS, Lima MF, et al. Effects of a mycophenolate mofetil–based immunosuppressive regimen in Chagas' heart transplant recipients. Transplantation 2007;84:441-2. 48. Bocchi EA, Fiorelli A. The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. Ann Thorac Surg 2001;71:1833-8. 49. Vilas-Boas F, Feitosa GA, Soares MBP, et al. Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas' disease. Arq Bras Cardiol 2006;87:159-66. 50. Talvani A, Rocha MOC, Cogan J, et al. Brain natriuretic peptide and left ventricular dysfunction in chagasic cardiomyopathy. Mem Inst Oswaldo Cruz 2004;99:645-9. 51. Bestetti RB. Predictors of unfavourable prognosis in chronic Chagas' disease. Trop Med Int Health 2001;6:476-83.
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The treatment of chronic heart failure secondary to Chagas disease has been based on extrapolation of data achieved in the treatment of non–Chagas disease heart failure. Because β-blockers decrease the incidence of sudden cardiac death in non–Chagas disease heart failure and sudden cardiac death occurs preferentially in patients with mild Chagas disease heart failure, β-blockers may be administered first to class I/II patients with Chagas disease heart failure. In advanced Chagas disease heart failure, angiotensin-converting enzyme inhibitor and diuretics may be given at first to compensate for congestive symptoms. After clinical status improvement, β-blockers should be given at targeted doses, if necessary reducing angiotensin-converting enzyme inhibitor doses. Primary and secondary prevention of sudden cardiac death may be accomplished with implantable cardioverter defibrillators because of the high recurrence of life-threatening arrhythmias despite amiodarone administration. In refractory heart failure, heart transplantation is the treatment of choice. (Am Heart J 2008;156:422-30.)
Although a marked decrease in the incidence of Chagas disease has been observed in the past decade in many countries of South America,1 it still is a major health problem and no longer confined to the American continent because of international immigration. In fact, about 100 million people are at risk of acquiring Chagas disease, 18 million are estimated to have the disease, and about 50,000 die of Chagas disease annually in South America.2 Chagas disease is caused by the protozoan Trypanosoma cruzi, which is transmitted to humans through the feces of a reduvidii bug.1 Chagas cardiomyopathy is the most frequent clinical manifestation of Chagas disease, affecting about 30% of infected patients 10 to 20 years after initial infection.3 Chronic heart failure, sudden cardiac death, thromboembolism, arrhythmias and atrioventricular blocks, and chest pain are the protean clinical manifestations of Chagas cardiomyopathy.3-5 Chagas cardiomyopathy is the leading cause of chronic systolic heart failure in areas where the disease
From the aOutpatient Cardiomyopathy Service, Division of Cardiology, and bDepartment of Pathology, Hospital de Base, São José do Rio Preto Medical School, São José do Rio Preto City, Brazil. Submitted November 2, 2007; accepted April 29, 2008. Reprint requests: Reinaldo B. Bestetti, MD, PhD, Hospital de Base, Setor de Eletrocardiografia, Av. Faria Lima, 5544; 15090-000 São José do Rio Preto City, Brazil. E-mail: [email protected] 0002-8703/$ - see front matter © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.04.023
is endemic.6 Chronic heart failure secondary to Chagas cardiomyopathy affects 4% to 8% of outpatients living in areas where the disease is endemic,7,8 10% of patients of a hospital-based sample of a secondary referral center, and up to 76% of patients from a hospitalderived cohort of a tertiary referral center.9,10 The incidence of chronic heart failure in hospital-based cohorts is about 3% annually.11 To date, no randomized, double-blinded, placebocontrolled clinical trial evaluating the impact of a treatment modality on survival has been conducted on patients with Chagas disease heart failure. Thus, no evidence-based guideline to treat Chagas disease heart failure exists. In this overview, we focus on strategies to properly treat patients with Chagas disease heart failure in the contemporary era of heart failure treatment.
Search strategy and selection criteria We did a search in PubMed (www.pubmed.gov) for randomized trials evaluating mortality in patients with chronic heart failure secondary to Chagas cardiomyopathy from 1965 onward. We also did a search looking for articles dealing with treatment of chronic heart failure secondary to Chagas cardiomyopathy. We linked search terms “heart failure” and “treatment” with “Chagas' disease.” We ruled out articles that reported data for Chagas and non–Chagas disease heart failure. We identified 25 articles on Chagas disease heart failure treatment, which formed the basis of this work.
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Figure 1
A, Gross aspect of the heart from a patient with chronic heart failure secondary to Chagas cardiomyopathy showing right and left ventricular dilatation as well as left ventricular apical aneurysm (*). B, Histologic aspect of an explanted heart from a patient with end-stage chronic heart failure secondary to Chagas cardiomyopathy who had been treated with benznidazol. A chronic inflammatory infiltrate composed mainly of lymphocytic cells associated with foci of interstitial fibrosis can be seen (hematoxylin-eosin, original magnification ×100).
Pathophysiology of chronic heart failure secondary to Chagas cardiomyopathy The gross aspect of the heart in Chagas disease heart failure is characterized by chamber dilatation, mural thrombosis, and left ventricular apical aneurysm in the absence of concomitant obstructive coronary artery disease. The presence of the apical aneurysm poses patients with Chagas disease to an additional risk because life-threatening ventricular arrhythmias may arise from this site (Figure 1, A). Histologically, autopsy material12 as well as explanted hearts from patients with Chagas disease heart failure have revealed extensive foci of reparative fibrosis associated with chronic myocardial inflammation intermingled with areas of normal myocardium throughout the heart. Interestingly, T cruzi is seldom seen in the myocardium, as shown in Figure 1, B. As a result of this remodeling process, an irreversible systolic pump failure ensues, thus leading to neurohormonal activation. Increased levels of plasma renin activity and plasma noradrenaline, similar to those found in non–Chagas disease heart failure, have been observed in patients with chronic heart failure due to Chagas disease.13-15 In view of cardiac parasympathetic destruction,12 intracardiac autonomic dysfunction also occurs. In fact, increased release of adrenaline from the coronary sinus has been detected in patients with Chagas disease as compared to patients with non–Chagas disease heart failure.15 This might facilitate noradrenaline myocardial uptake,16 resulting in increased myocardial toxicity and subsequent ventricular remodeling, as observed in a rat model of catecholamine cardiomyopathy.17 Collectively, therefore,
these findings suggest that the neurohormonal profile of Chagas disease heart failure is similar to that seen in non– Chagas disease heart failure.
Clinical course of patients with Chagas disease heart failure Left-sided chronic heart failure is the most frequently found manifestation of Chagas disease heart failure, followed by bi-sided heart failure, sometimes with the predominance of right ventricular signs.3 Echocardiography usually reveals left ventricular dilatation, left ventricular systolic dysfunction, left ventricular apical aneurysm, and mural thrombus.18 A clinical picture consistent with overt isolated diastolic heart failure has not been detected in Chagas disease. Predictors of mortality for the subset of patients with Chagas disease heart failure are scanty. Systolic blood pressure, left ventricular ejection fraction, and maximal oxygen consumption rate have been found to be independent predictors of mortality for patients with Chagas disease with chronic heart failure.10,19,20 In the contemporary era of heart failure treatment, a prospective longitudinal cohort study carried out at our institution showed that lack of β-blocking agent use, left ventricular ejection fraction, New York Heart Association class IV, serum sodium levels, and digoxin use were independent predictors of all-cause mortality for patients with chronic heart failure due to Chagas disease.21 Outcome of patients with chronic heart failure secondary to Chagas cardiomyopathy is relentless and poorer than that observed in those with non–Chagas disease heart failure. An annual mortality rate as high as
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Table I. Major relevant studies evaluating neurohormonal axis, left ventricular function, and hemodynamic parameters carried out on patients with chronic heart failure due to Chagas disease Author No. of patients Year of publication Type of study Treatment intervention Duration of study Outcome
Roberti et al24
Szajnbock et al25
Botoni et al26
Davila et al28
Manço et al33
Khoury et al34
15 1992 RPCT
20 1993 NRCT
9 2002 UCS
10 1974 UCS
13 1996 NRCT
Captopril, 150 mg/d
Ena, 5-10 mg/d
42 2007 Ena: UCS; Car: RPCT Ena: 40 mg/d; Car: 50 mg/d
Metoprolol, 50 mg/d
IV lanatosideo C 0.4-1.2 mg
6 wk Decreased HR, UNE, couplets/ 24 h (P b .05).
8 wk Decreased E/A wave
Metil digoxina: 0.02 mg/kg; 6/6 for 24 h 24 h Decreased PNE (P b .008), PAldo (P b .01)
16 wk 10 wk 1h Increased LVEF Decreased PCWP, Phase 1: Ena (P b .05), decreased increased CO increased LVEF LVSD (P b .04) (P = .02), decreased serum BNP (P = .03),
RPCT, Randomized placebo controlled trial; NRCT, nonrandomized controlled trial; Ena, enalapril; UCS, uncontrolled study; Car, carvedilol; IV, intravascular; HR, heart rate (beat/ min); UNE, urinary norepinephrine (pg/mL); E/A, relation between waves E and A on Doppler echocardiography; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure (mm Hg); LVSD, left ventricular systolic dimension; CO, cardiac output (L/min); PNE, plasma norepinephrine (pg/mL); PAldo, plasma aldosterone (pg/mL).
20% may be observed in patients with this condition20 even in the contemporary era.21
Management of patients with Chagas disease with chronic heart failure
heart failure secondary to Chagas cardiomyopathy who tolerate target doses of angiotensin-converting enzyme inhibitors (ACEIs)6 and perhaps β-blocking agent therapy.23 Therefore, control of dietary sodium ingestion should be made with some caution in patients with Chagas disease heart failure.
Nonpharmacological treatment A major point of attention regarding the dietetic regimen of patients with chronic heart failure secondary to Chagas cardiomyopathy is related to magnesium ingestion. In fact, low serum magnesium levels can be found in about 33% of patients with chronic heart failure secondary to Chagas cardiomyopathy, whereas the percentage of patients with this condition with low muscle magnesium content is still higher (66%). In these patients, low magnesium levels have been associated with either clinical signs of digitalis toxicity or lifethreatening ventricular arrhythmias on the 12-lead electrocardiogram.22 Because patients with Chagas disease are usually from a low socioeconomic class, thus having a high likelihood of poor nutrition, mainly during episodes of overt heart failure, a dietetic regimen rich in magnesium content would be desirable to patients with chronic Chagas disease heart failure. Another aspect that deserves further consideration is salt ingestion restriction. A low-sodium diet has frequently been used in the treatment of Chagas disease heart failure. Nonetheless, low levels of systemic arterial pressure have usually been found in patients with Chagas disease in comparison to patients with non– Chagas disease heart failure.23 Because patients with chronic heart failure usually have increased urinary sodium losses, salt ingestion reduction may further decrease low serum sodium levels, thus predisposing patients with Chagas disease heart failure to systemic arterial hypotension. This fact might account, at least in part, for the low percentage of patients with chronic
Pharmacological treatment Angiotensin-converting enzyme inhibitors have largely been used in the treatment of patients with chronic heart failure secondary to Chagas cardiomyopathy. However, a few studies have evaluated the role of ACEIs in the treatment of patients with Chagas disease with chronic heart failure. A randomized trial conducted on New York Heart Association class IV patients has shown a beneficial effect of captopril on decreasing heart rate, urinary catecholamine levels, plasma renin activity, and ventricular couplets (Table I). A similar beneficial effect of enalapril on left ventricular diastolic function has been reported by Szajnbock et al25 (Table I). Botoni et al26 recently reported that high doses of enalapril increase left ventricular ejection fraction, improve quality of life, and decrease serum brain natriuretic peptide (BNP) and chemokines levels, as shown in Table I. β-Blocking agents are promising in the treatment of Chagas disease heart failure. Experimentally, metoprolol was able to reverse eletrocardiographic changes consistent with T cruzi–induced rat chronic Chagas heart disease.27 Davila et al28 clearly demonstrated that longterm small doses of metoprolol improved clinical status, increased systemic arterial pressure, and increased left ventricular systolic function in the midterm follow-up (Table I). Recently, Botoni et al26 have shown a marginal positive effect of carvedilol on left ventricular ejection fraction after the renin-angiotensin system blocking (Table I). Importantly, neither bradycardia nor systemic arterial hypotension was reported in such studies.26,28
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After having blocked the renin-angiotensin system with captopril in patients with chronic heart failure secondary to Chagas cardiomyopathy, we were able to add β-blockers only to 37% of such patients because of the appearance of symptomatic systemic arterial hypotension.21 Our results are in line with those reported by Braga et al,23 who were able to give β-blocking agents only to 39% of patients with chronic heart failure secondary to Chagas cardiomyopathy. Thus, it is conceivable that a general, unselected population of patients with Chagas disease heart failure, in contrast to patients with non–Chagas disease enrolled in randomized clinical trials, will not be able to tolerate the target doses of β-blockers and ACEIs used in major trials. Based on these facts, and because sudden cardiac death is more frequently observed in patients with Chagas disease with mild chronic heart failure than in those with advanced chronic heart failure,11 ACEIs increase left ventricular ejection fraction mainly in patients with a basal left ventricular ejection fraction b45%,26 β-blockers may decrease sudden cardiac death in non–Chagas disease heart failure,29 and treatment of heart failure can be initiated with either ACEI inhibitors or β-blockers in the setting of non–Chagas disease heart failure.30 It is conceivable that β-blockers might be administered firstly than ACEIs in New York Heart Association Functional class I and II patients with Chagas disease in. Because the neurohormonal activation is similar to that found in non– Chagas disease heart failure, it is reasonable to achieve target doses of β-blockers (50 mg/d to carvedilol, 200 mg/d to metoprolol CR/XL, and 10 mg/d to bisoprolol) in patients with Chagas disease heart failure. In the case patients are not able to tolerate these doses because of side effects (symptomatic systemic arterial hypotension and/or drug-induced asthma and/or renal failure), daily doses of such drugs should be reduced. The β-blocking agent should be withdrawn only if side effects still persist. Nonetheless, we concede that such a proposition needs to be tested in a prospective randomized trial. In patients with advanced chronic heart failure secondary to Chagas cardiomyopathy (New York Heart Association classes III or IV), furosemide is usually necessary to alleviate congestive symptoms. Nonetheless, the potential negative impact of long-term furosemide administration has never been appreciated in these patients. Furthermore, ACEIs might be given first than a βblocking agent not only because of the safety and efficacy of ACEIs in patients with Chagas cardiomyopathy with advanced heart failure but also because of the potential for β-blockers to aggravate congestive symptoms in patients with this condition. As previously discussed, it is conceivable that up to 60% of patients will not be able to tolerate a β-blocker agent after a target dose of ACEI (enalapril = 20 mg/d, captopril = 75 mg/d) is achieved. In this circumstance, it might be necessary to reduce the
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daily dose of ACEI in order that the β-blocker agent could be given. This approach might be supported by studies showing that small doses of ACEI have the same beneficial impact on mortality than target doses used in trials enrolling patients with non–Chagas disease heart failure.31,32 It is noteworthy that a daily dose of carvedilol as low as 6.25 mg may have a protective effect in patients with Chagas cardiomyopathy with chronic heart failure.21 Spironolactone combined with ACEI has recently been demonstrated to have a beneficial effect on the neurohormonal activation in patients with mild heart failure due to Chagas disease.26 It is unclear whether spironolactone would be beneficial to patients with chronic heart failure secondary to Chagas cardiomyopathy not taking ACEIs. In non–Chagas disease heart failure, it is now well established that spironolactone administration improves survival. Although no study evaluating the effects of spironolactone in patients with advanced heart failure due to Chagas disease is available, it would be reasonable to administer it to patients with advanced and milder forms of Chagas disease heart failure, mostly if in combination with ACEIs. Digoxin is another drug that has long been used in the treatment of patients with advanced chronic heart failure secondary to Chagas cardiomyopathy. Acute digitalization produces a salutary effect on the hemodynamic parameters, decreasing right atrium pressure, right ventricular pressure, and pulmonary capillary wedge pressure and increasing systemic arterial pressure and cardiac output.33 Furthermore, acute digoxin administration has been shown to decrease plasma levels of noradrenaline, aldosterone, and renin activity.34 Nonetheless, potential for toxicity is great in patients with chronic heart failure due to Chagas disease in view of the severity of underlying myocardial lesions throughout the myocardium12 as well as the compromise of the cardiac conducting system.3 In clinical practice, however, neither advanced atrioventricular block nor ventricular arrhythmias have been observed in patients with chronic heart failure due to Chagas disease on chronic digital use whenever this drug is given cautiously.35 However, a recent observational study has shown that chronic digoxin use is a predictor of all-cause mortality.21 Thus, measurement of digoxin serum levels would be desirable in patients with Chagas disease heart failure treated with digoxin. Anticoagulation to prevent stroke remains controversial in patients with Chagas disease heart failure. The incidence of cardioembolic stroke is low in a general, unselected hospital-based cohort of patients with chronic Chagas heart disease.36 Carod-Artal et al37 have shown that left ventricular apical aneurysm, heart failure, and arrhythmias are major contributors to independently predict stroke in patients with chronic Chagas disease. Studies performed specifically in patients with chronic heart failure due to Chagas disease are virtually lacking.
426 Bestetti et al
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Figure 2
Electrogram from a patient with Chagas disease heart failure treated with ICD. Nonsustained VT was detected on 24-hour Holter monitoring, and an inducible episode of sustained VT was found at electrophysiologic testing. An episode of VF during follow-up, not preceded by sustained VT, can be seen. AF, Atrial fibrillation.
Thus, at the present time, taking into consideration the cost-effectiveness of anticoagulation in patients with low socioeconomic status, it would be prudent to recommend anticoagulation to patients with Chagas disease heart failure with left ventricular apical aneurysm with mural thrombus, atrial fibrillation, or previous stroke. Benznidazol has been claimed to have a beneficial effect on disease progression in patients with Chagas disease.38 However, no study has addressed the role of benznidazol in patients with chronic Chagas disease chronic heart failure.
Surgical treatment Another major point in the treatment of patients with chronic heart failure secondary to Chagas cardiomyopathy is sudden cardiac death prevention. In this regard, electrophysiologic testing is crucial to mortality risk stratification and proper treatment to avert sudden cardiac death. Another potential tool to properly manage sudden cardiac death in patients with Chagas disease heart failure is heart rate variability. Heart rate variability measurements are well-established predictors of total mortality and sudden cardiac death in patients with non– Chagas disease heart failure.39 Nonetheless, the value of heart rate variability to predict cardiac death in patients
with Chagas disease with chronic heart failure has not yet been established. It would be desirable to measure indices of heart rate variability in patients with this condition not only to refine mortality risk stratification but also to guide the impact of therapeutic modalities on autonomic dysfunction. Nonsustained ventricular tachycardia (VT), which has been detected in 89% of patients with Chagas cardiomyopathy with chronic heart failure,40 has been shown to be a predictor of all-cause mortality in patients with mild9 left ventricular dysfunction secondary to Chagas cardiomyopathy. Induction of sustained VT at programed ventricular stimulation in patients with Chagas disease heart failure with nonsustained VT receiving amiodarone or sotalol predicts a dismal prognosis.41 Thus, the efficacy of amiodarone for primary prevention of sudden cardiac death in patients with Chagas disease heart failure is limited. This might be explained by ventricular fibrillation (VF) not preceded by degeneration of sustained VT can be found in up to 37% of patients with chronic Chagas heart disease42 despite amiodarone therapy in contrast to what has been observed in patients with non–Chagas disease. In addition, in non–Chagas disease heart failure, amiodarone has been shown to have no beneficial effect on all-cause mortality.43 Based on these facts, it is
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plausible to recommend implantable cardioverter defibrillator (ICD) therapy for primary prevention of sudden cardiac death in patients with Chagas disease with chronic heart failure and a left ventricular ejection fraction b30% because of the high risk of primary VF, as shown in Figure 2, and in keeping with current guidelines for non–Chagas disease dilated cardiomyopathy. In patients with left ventricular ejection fraction N30% and nonsustained VT at Holter monitoring, however, sudden death risk stratification with electrophysiologic testing is paramount. Those patients with inducible VT might be better treated with ICD. For the remaining patients, amiodarone should be given to those with arrhythmiainduced symptoms. Sustained VT is a frequent complication of chronic Chagas heart disease.44 Almost all patients will experience resurgence of life-threatening ventricular arrhythmias, including VF, within 2 years of the index event despite treatment with amiodarone and/or a β-blocking agent.42 Furthermore, in patients with Chagas disease with life-threatening ventricular arrhythmias, sudden cardiac death may be prevented by ICD therapy.45 Thus, ICD therapy seems to be preferable for secondary prevention of sudden cardiac death for patients with chronic heart failure due to Chagas disease. However, when this device-based therapy is unavailable, an alternative approach is to give amiodarone and βblocking agent, followed by an electrophysiologic testing. Patients with no inducible life-threatening ventricular arhythmias or those with inducible VT well tolerated hemodynamicaly may not receive ICD therapy.46 Data concerning resyncronization therapy in Chagas disease heart failure are lacking. At the present time, it would be reasonable to offer resyncronization therapy for patients with advanced chronic heart failure due to Chagas disease, proper medical therapy (target doses of β-blockers and ACEI), lengthening of the QRS complex N120 milliseconds on 12-lead electrocardiogram, and documenting intraventricular dyssyncrony on Tissue Doppler Imaging, as recommended for patients with non–Chagas disease heart failure. Orthotopic heart transplantation is a feasible treatment for selected patients with refractory heart failure secondary to Chagas cardiomyopathy. One study has shown that the median number of bacterial infection episodes per patient is 0.5 in Chagas heart transplant recipients and 1.0 in non–Chagas heart transplant recipients (P b .05). Therefore, the incidence of infection after heart transplantation is lower in Chagas than in non– Chagas heart transplant recipients.47 Perhaps this fact may account, at least in part, for why outcome after heart transplantation is better in Chagas than in non–Chagas heart transplant recipients.48 Vilas-Boas et al49 implanted bone marrow stem cells in the myocardium of 28 patients with refractory chronic heart failure secondary to Chagas cardiomyopathy. They
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Table II. Potential differences in the treatment of patients with Chagas disease heart failure in comparison to patients with non– Chagas disease heart failure
Diet rich in magnesium content Spironolactone in combination with ACEI to NYHA class I/II patients Low tolerability to ACEI target doses β-Blocker first than ACEI CRT efficacy ICD therapy for patients with LVEF N30%, NYHA class I/II, and inducible VT
Chagas disease
Non–Chagas disease
Necessary Yes
Unknown Unknown
Yes Yes Unknown Yes
No Likely Yes Controversial
NYHA, New York Heart Association; CRT, cardiac resyncronization therapy; LVEF, left ventricular ejection fraction.
have observed a modest increase in left ventricular ejection fraction, improvement in clinical status, improvement in indices of quality of life, and an increase in the distance walked during 6 minutes 2 months after the procedure. Whether stem cell implantation will have a place in the treatment of Chagas disease heart failure remains to be determined. Table II summarizes potential differences in the management of patients with Chagas disease heart failure in comparison to patients with non–Chagas disease heart failure. Figure 3 illustrates our suggestion to treat patients with chronic heart failure due to Chagas disease. Class I patients may be identified with either echocardiography18 or BNP50 measurements in areas where the disease is endemic. However, in distant, rural areas, where the conduct of such tests is not feasible, clinical status and/or male sex may be of value to identify asymptomatic left ventricular dysfunction.51 Such patients may be firstly treated with β-blockers, as recommended for non–Chagas disease asymptomatic left ventricular dysfunction. Class II patients may also be given β-blockers first, not only to block the ventricular remodeling process but also to avert sudden cardiac death. Class III patients should initially be treated with diuretics, ACEIs, and if really necessary, digoxin (with monitoring of digoxin serum levels). After clinical compensation, a β-blocking agent must be added to treatment. Class IV patients must be treated with diuretics, ACEI, and digoxin. In refractory class IV symptoms, intravenous sodium nitroprusside may replace ACEI to further decrease left ventricular enddiastolic pressure and ameliorates congestive symptoms. Primary prophylaxis of sudden cardiac death in patients with a left ventricular ejection fraction b30% may be accomplished with ICD treatment. Patients with a left ventricular ejection fraction N30% and nonsustained VT should undergo electrophysiologic testing. In those patients with inducible life-threatening ventricular arrhythmias, ICD-based therapy may be useful. Anticoagulation is warranted by patients with left ventricular
428 Bestetti et al
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Figure 3
Suggestion of a strategy to treat patients with Chagas disease with chronic heart failure. LVEF, Left ventricular ejection fraction; NSVT, nonsustained VT; EPT, electrophysiologic testing; Dys, dyssynchrony; RCT, resynchronization therapy.
apical aneurysm with a mural thrombus, atrial fibrillation, and/or a previous stroke.
Conclusions Treating Chagas disease heart failure is a major challenge for physicians working in areas where the disease is endemic because of lack of evidence-based medicine support to improve survival. Target doses of βblockers and ACEIs achieved in major trials conducted on
patients with non–Chagas disease are the mainstay of pharmacological treatment of patients with chronic heart failure due to Chagas disease . Primary and secondary prevention of sudden cardiac death can be accomplished with ICD therapy. Heart transplantation is the preferable treatment for patients with end-stage heart failure. We are indebted to Adília Maria Pires Sciarra, MSc, for revising the English text.
American Heart Journal Volume 156, Number 3
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